Discovery of novel series of benzoic acid derivatives containing biphenyl ether moiety as potent and selective human beta(3)-adrenergic receptor agonists: Part IV

Identification and SAR study of novel series of beta(3)-AR agonists with benzoic acid are described. Conversion of ether linkage position of phenoxybenzoic acid derivative 2b led to compound 7b with moderate beta(3)-AR activity. Further modification in right, center and left parts of compound 7b was investigated to improve the beta(3)-AR potency and selectivity. Compounds 7g and 7k, with the bulky aliphatic-substituted group at 2-position of benzoic acid moiety, were identified as potent and selective beta(3)-AR agonists. In addition, in vivo efficacy of compounds 7g and 7k was exhibited on dog OAB model.     

Repeated assessments of informed consent comprehension among HIV-infected participants of a three-year clinical trial in Botswana

Background

Informed consent (IC) has been an international standard for decades for the ethical conduct of clinical trials. Yet frequently study participants have incomplete understanding of key issues, a problem exacerbated by language barriers or lack of familiarity with research concepts. Few investigators measure participant comprehension of IC, while even fewer conduct interim assessments once a trial is underway.

Methods and Findings

We assessed comprehension of IC using a 20-question true/false quiz administered in 6-month intervals in the context of a placebo-controlled, randomized trial for the prevention of tuberculosis among HIV-infected adults in Botswana (2004–2009). Quizzes were offered in both Setswana and English. To enroll in the TB trial, participants were required to have ≥16/20 correct responses. We examined concepts understood and the degree to which understanding changed over three-years. We analyzed 5,555 quizzes from 1,835 participants. The participants'' highest education levels were: 28% primary, 59% secondary, 9% tertiary and 7% no formal education. Eighty percent of participants passed the enrollment quiz (Quiz1) on their first attempt and the remainder passed on their second attempt. Those having higher than primary education and those who took the quiz in English were more likely to receive a passing score on their first attempt (adjusted odds ratios and 95% confidence intervals, 3.1 (2.4–4.0) and 1.5 (1.2, 1.9), respectively). The trial''s purpose or procedures were understood by 90–100% of participants, while 44–77% understood randomization, placebos, or risks. Participants who failed Quiz1 on their initial attempt were more likely to fail quizzes later in the trial. Pass rates improved with quiz re-administration in subsequent years.

Conclusions

Administration of a comprehension quiz at enrollment and during follow-up was feasible in a large, international collaboration and efficiently determined IC comprehension by trial participants. Strategies to improve understanding of concepts like placebos and randomization are needed. Comprehension assessments throughout a study may reinforce key concepts.     

Risk factors for non-adherence and loss to follow-up in a three-year clinical trial in Botswana

Background

Participant non-adherence and loss to follow-up can compromise the validity of clinical trial results. An assessment of these issues was made in a 3-year tuberculosis prevention trial among HIV-infected adults in Botswana.

Methods and Findings

Between 11/2004–07/2006, 1995 participants were enrolled at eight public health clinics. They returned monthly to receive bottles of medication and were expected to take daily tablets of isoniazid or placebo for three years. Non-adherence was defined as refusing tablet ingestion but agreeing to quarterly physical examinations. Loss to follow-up was defined as not having returned for appointments in ≥60 days. Between 10/2008–04/2009, survey interviews were conducted with 83 participants identified as lost to follow-up and 127 identified as non-adherent. As a comparison, 252 randomly selected adherent participants were also surveyed. Multivariate logistic regression analysis was used to identify associations with selected risk factors. Men had higher odds of being non-adherent (adjusted odds ratio (AOR), 2.24; 95% confidence interval [95%CI] 1.24–4.04) and lost to follow-up (AOR 3.08; 95%CI 1.50–6.33). Non-adherent participants had higher odds of reporting difficulties taking the regimen or not knowing if they had difficulties (AOR 3.40; 95%CI 1.75–6.60) and lower odds associated with each year of age (AOR 0.95; 95%CI 0.91–0.98), but other variables such as employment, distance from clinic, alcohol use, and understanding study requirements were not significantly different than controls. Among participants who were non-adherent or lost to follow-up, 40/210 (19.0%) reported that they stopped the medication because of work commitments and 33/210 (15.7%) said they thought they had completed the study.

Conclusions

Men had higher odds of non-adherence and loss to follow-up than women. Potential interventions that might improve adherence in trial participants may include:targeting health education for men, reducing barriers, clarifying study expectations, educating employers about HIV/AIDS to help reduce stigma in the workplace, and encouraging employers to support employee health.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00164281","term_id":"NCT00164281"}}NCT00164281     

Discovery of highly potent and selective biphenylacylsulfonamide-based β3-adrenergic receptor agonists and molecular modeling based on the solved X-ray structure of the β2-adrenergic receptor: Part 6

As an extension of research, we have investigated modification of left-hand side (LHS) of biphenyl analogues containing an acylsulfonamide moiety in the development of potent and selective human β₃-adrenergic receptor (AR) agonists. Result of structure–activity relationships (SAR) and cassette-dosing evaluation in dogs showed that the hydroxynorephedrine analogue 16 had an excellent balance of in vitro and in vivo potency with pharmacokinetic profiles. In addition, to facilitate structure-based drug design (SBDD), we also have performed a docking study of biphenyl analogues based on the X-ray structure of the β₂-adrenergic receptor.